Methods of performing cycloadditions, reaction mixtures, and methods of performing asymmetric catalytic reactions

ABSTRACT

Methods of performing cycloadditions are described that include (a) combining a first reactant and a second reactant in a hydrogen bonding solvent to form a reaction mixture; and (b) reacting the first reactant and the second reactant to form a cycloadduct. Methods of performing asymmetric catalytic reactions are also described that include (a) combining a first reactant, a second reactant, and a catalytic amount of a chiral hydrogen-bond donor in a solvent to form a reaction mixture; and (b) reacting the first reactant and the second reactant to form an enantiomeric excess of a reaction product. Reaction mixtures corresponding to these methods are also described.

RELATED APPLICATIONS

This application is a divisional of prior application Ser. No.10/629,537, filed Jul. 28, 2003 (now U.S. Pat. No. 7,230,125), whichclaims the benefit of priority under 35 U.S.C. §119(e) to U.S.provisional patent application Ser. No. 60/398,696, filed Jul. 26, 2002,the entire contents of both of which are incorporated herein byreference, except that in the event of any inconsistent disclosure ordefinition from the present application, the disclosure or definitionherein shall be deemed to prevail.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This application was funded in part under National Institutes of Healthgrant NIH R01-GM-55998. The U.S. Government may have rights in thisinvention.

FIELD OF THE INVENTION

The present invention relates generally to enantioselective catalysisand to cycloaddition reactions.

BACKGROUND

The [4+2] cycloaddition reaction between dienes and compounds containinga carbonyl group provides one of the most direct methods available forthe synthesis of six-membered oxygen-containing heterocycles.

The hetero Diels-Alder (HDA) reaction has been studied extensively as apotential route for the preparation of oxygen-containing heterocycles, aclass of biologically important molecules. Notwithstanding, the scope ofthe HDA reaction remains extremely limited. Nearly all such knowncycloadditions have been reported using aldehydes and, even then,require highly specialized reaction conditions, such as hightemperatures, high pressures, or Lewis acid catalysis.

For steric and electronic reasons, the ketone group is a substantiallyless reactive heterodienophile as compared to the aldehyde group. As aresult, there have been extremely few reports of successful HDAreactions using simple ketones. Moreover, the use of ketones in thesetypes of reactions is far from having general applicability.Accordingly, the development of a HDA reaction that is suitable for usewith heterodienophiles such as ketones would be extremely advantageous.

Conventional methods for catalyzing asymmetric Diels-Alder reactionstypically use metals and Lewis acids, which are often undesirable fromthe point of view of cost as well as safety (e.g., the presence of traceamounts of residual metals in the Diels-Alder cycloadduct may limit thepharmaceutical use of that compound due to strict federal regulations).Accordingly, the development of metal-free asymmetric variants of theDiels-Alder and HDA reaction would be highly desirable.

SUMMARY

The scope of the present invention is defined solely by the appendedclaims, and is not affected to any degree by the statements within thissummary.

By way of introduction, a method of performing a cycloaddition reactionembodying features of the present invention includes: (a) combining afirst reactant and a second reactant in a hydrogen bonding solvent toform a reaction mixture; and (b) reacting the first reactant and thesecond reactant to form a cycloadduct.

A first reaction mixture embodying features of the present inventionincludes: (a) a diene; (b) a dienophile; and (c) a hydrogen bondingsolvent.

A method of performing an asymmetric catalytic reaction embodyingfeatures of the present invention includes: (a) combining a firstreactant, a second reactant, and a catalytic amount of a chiralhydrogen-bond donor in a solvent to form a reaction mixture; and (b)reacting the first reactant and the second reactant to form anenantiomeric excess of a reaction product.

A first reaction mixture embodying features of the present inventionincludes: (a) a first reactant selected from the group consisting ofdiene and an alkyne; (b) a second reactant selected from the groupconsisting of a dienophile and an aldehyde, wherein the second reactantis complementary in reactivity to the first reactant; (c) a solvent; and(d) a catalytic amount of a chiral hydrogen-bond donor.

An improvement embodying features of the present invention to a methodof performing a hetero-Diels-Alder reaction includes reacting a dienewith a heterodienophile in a hydrogen bonding solvent selected from thegroup consisting of chloroform, t-butanol, i-propanol, 2-butanol, andcombinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 of U.S. Pat. No. 7,230,125 shows a schematic representation of aC—H—O hydrogen bond formed between chloroform and the oxygen atom of acarbonyl group.

FIG. 2 of U.S. Pat. No. 7,230,125 shows a schematic representation of ahydrogen bond formed between the methoxy oxygen of2-methoxycyclohexanone and the proton of the hydroxyl group of analcohol solvent.

FIG. 3 of U.S. Pat. No. 7,230,125 shows a group of metal-containing andLewis acid catalysts that have been used for conventional HDA reactions.

FIG. 4 of U.S. Pat. No. 7,230,125 shows three chiral acidichydrogen-bond donors, each having one acidic proton, which were examinedin accordance with the development of the present invention.

FIG. 5 of U.S. Pat. No. 7,230,125 shows two models for chiral diolactivation in accordance with the present invention.

FIG. 6 of U.S. Pat. No. 7,230,125 shows a series of chiral diols testedin accordance with the development of the present invention.

FIG. 7 of U.S. Pat. No. 7,230,125 shows a generic structure of TADDOL.

FIG. 8 of U.S. Pat. No. 7,230,125 shows components for the preparationof TADDOLs and their analogues.

FIG. 9 of U.S. Pat. No. 7,230,125 shows the staggered, C₂-symmetricconformation of the TADDOL skeleton.

FIG. 10 of U.S. Pat. No. 7,230,125 shows a series of 1-halo-naphthylderivatives embodying features of the present invention.

FIG. 11 of U.S. Pat. No. 7,230,125 shows TADDOL structure with a genericacetonide in accordance with the present invention.

FIG. 12 of U.S. Pat. No. 7,230,125 shows a ¹H NMR spectrum ofspiro-dihydropyrone 6a.

FIG. 13 of U.S. Pat. No. 7,230,125 shows a ¹³C NMR spectrum ofspiro-dihydropyrone 6a.

FIG. 14 of U.S. Pat. No. 7,230,125 shows a ¹H NMR spectrum ofspiro-dihydropyrone 6b.

FIG. 15 of U.S. Pat. No. 7,230,125 shows a ¹³C NMR spectrum ofspiro-dihydropyrone 6b.

FIG. 16 of U.S. Pat. No. 7,230,125 shows a ¹H NMR spectrum ofspiro-dihydropyrone 6c.

FIG. 17 of U.S. Pat. No. 7,230,125 shows a ¹³C NMR spectrum ofspiro-dihydropyrone 6c.

FIG. 18 of U.S. Pat. No. 7,230,125 shows a ¹H NMR spectrum ofspiro-dihydropyrone 6d.

FIG. 19 of U.S. Pat. No. 7,230,125 shows a ¹³C NMR spectrum ofspiro-dihydropyrone 6d.

FIG. 20 of U.S. Pat. No. 7,230,125 shows a ¹H NMR spectrum ofspiro-dihydropyrone 6e.

FIG. 21 of U.S. Pat. No. 7,230,125 shows a ¹³C NMR spectrum ofspiro-dihydropyrone 6e.

FIG. 22 of U.S. Pat. No. 7,230,125 shows a ¹H NMR spectrum of a majorisomer of spiro-dihydropyrone 6f.

FIG. 23 of U.S. Pat. No. 7,230,125 shows a ¹³C NMR spectrum of a majorspiro-dihydropyrone 6f.

FIG. 24 of U.S. Pat. No. 7,230,125 shows a ¹H NMR spectrum of a minorisomer of spiro-dihydropyrone 6f.

FIG. 25 of U.S. Pat. No. 7,230,125 shows a ¹³C NMR spectrum of a minorspiro-dihydropyrone 6f.

FIG. 26 of U.S. Pat. No. 7,230,125 shows a ¹H NMR spectrum ofspiro-dihydropyrone 6g.

FIG. 27 of U.S. Pat. No. 7,230,125 shows a ¹³C NMR spectrum ofspiro-dihydropyrone 6g.

FIG. 28 of U.S. Pat. No. 7,230,125 shows a ¹H NMR spectrum ofspiro-dihydropyrone 6h.

FIG. 29 of U.S. Pat. No. 7,230,125 shows a ¹³C NMR spectrum ofspiro-dihydropyrone 6h.

FIG. 30 of U.S. Pat. No. 7,230,125 shows a ¹H NMR spectrum ofspiro-dihydropyrone 6i.

FIG. 31 of U.S. Pat. No. 7,230,125 shows a ¹³C NMR spectrum ofspiro-dihydropyrone 6i.

FIG. 32 of U.S. Pat. No. 7,230,125 shows a ¹H NMR spectrum ofspiro-dihydropyrone 6j.

FIG. 33 of U.S. Pat. No. 7,230,125 shows a ¹³C NMR spectrum ofspiro-dihydropyrone 6j.

FIG. 34 of U.S. Pat. No. 7,230,125 shows a ¹H NMR spectrum ofspiro-dihydropyrone 6k.

FIG. 35 of U.S. Pat. No. 7,230,125 shows a ¹³C NMR spectrum ofspiro-dihydropyrone 6k.

FIG. 36 of U.S. Pat. No. 7,230,125 shows an HPLC scan of a singleenantiomer of 4a.

FIG. 37 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4a.

FIG. 38 of U.S. Pat. No. 7,230,125 shows an HPLC scan of a singleenantiomer of 4b.

FIG. 39 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4b.

FIG. 40 of U.S. Pat. No. 7,230,125 shows an HPLC scan of a singleenantiomer of 4c.

FIG. 41 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4c.

FIG. 42 of U.S. Pat. No. 7,230,125 shows an HPLC scan of a singleenantiomer of 4d.

FIG. 43 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4d.

FIG. 44 of U.S. Pat. No. 7,230,125 shows an HPLC scan of a singleenantiomer of 4e.

FIG. 45 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4e.

FIG. 46 of U.S. Pat. No. 7,230,125 shows an HPLC scan of a singleenantiomer of 4f.

FIG. 47 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4f.

FIG. 48 of U.S. Pat. No. 7,230,125 shows an HPLC scan of a singleenantiomer of 4g.

FIG. 49 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4g.

FIG. 50 of U.S. Pat. No. 7,230,125 shows an HPLC scan of a singleenantiomer of 4h.

FIG. 51 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4h.

FIG. 52 of U.S. Pat. No. 7,230,125 shows an HPLC scan of a singleenantiomer of 4i.

FIG. 53 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4i.

FIG. 54 of U.S. Pat. No. 7,230,125 shows an HPLC scan of a singleenantiomer of 4j.

FIG. 55 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4j.

DETAILED DESCRIPTION

The first general method for performing HDA reactions with unactivatedketones has been discovered and will be described below. This methodinvolves a hitherto unrecognized hydrogen-bond promoted acceleration ofthe HDA reaction.

In addition, catalysts have been discovered and will be described belowthat enable an enantioselective version of the HDA reaction usingunactivated ketones.

Furthermore, it has been discovered that the above-mentioned catalystsmay also be used in a variety of other enantioselective reactions, suchas traditional Diels-Alder reactions at the olefin portions ofα,β-unsaturated carbonyl compounds, as well as enantioselectivenon-cycloaddition reactions including the alkynylation of aldehydes.

Throughout this description and in the appended claims, the followingdefinitions are to be understood:

The phrase “complementary to” refers to the reactivity of a firstreagent being complementary to the reactivity of a second reagent, suchthat the first reagent and the second reagent are configured to coupletogether in a cycloaddition reaction. By way of illustration, arepresentative pair of complementary first and second reagentscorresponds to a diene and a dienophile, which may be coupled togetherin a Diels-Alder [4+2] cycloaddition to form a 6-membered cycloadduct.

The term “diene” refers to a molecule containing at least two conjugateddouble bonds. The atoms forming the double bonds may be carbon atoms,heteroatoms, or a combination thereof. The double bonds may besubstituted (e.g., with one or more electron donating or electronwithdrawing groups) or unsubstituted. Preferably, the double bonds aresubstituted with one or more electron donating groups.

The term “dienophile” refers to a molecule containing at least oneunsaturated bond (e.g., a double bond, a triple bond). The atoms formingthe unsaturated bond may be carbon atoms, heteroatoms, or a combinationthereof. The unsaturated bond may be substituted (e.g., with one or moreelectron donating or electron withdrawing groups) or unsubstituted.

The term “alkyl” refers to a substituted or unsubstituted, straight,branched or cyclic hydrocarbon chain containing, preferably, from 1 to20 carbon atoms. Representative examples of unsubstituted alkyl groupsfor use in accordance with the present invention include but are notlimited to methyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl,iso-butyl, tert-butyl, sec-butyl, cyclobutyl, pentyl, cyclopentyl,hexyl, cyclohexyl, and the like.

The term “alkenyl” refers to a substituted or unsubstituted, straight,branched or cyclic, unsaturated hydrocarbon chain that contains at leastone double bond and, preferably, from 2 to 20 carbon atoms.Representative unsubstituted alkenyl groups for use in accordance withthe present invention include but are not limited to ethenyl or vinyl(—CH═CH₂), 1-propenyl, 2-propenyl or allyl (—CH₂—CH═CH₂), 1,3-butadienyl(—CH═CHCH═CH₂), 1-butenyl (—CH═CHCH₂CH₃), hexenyl, pentenyl,1,3,5-hexatrienyl, and the like. Preferred cycloalkenyl groups are thosehaving from five to eight carbon atoms and at least one double bond.Representative cycloalkenyl groups for use in accordance with thepresent invention include but are not limited to cyclohexadienyl,cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl,cyclohexadienyl, cycloheptadienyl, cyclooctatrienyl, and the like.

The term “alkoxy” refers to a substituted or unsubstituted —O-Alkylgroup. Representative unsubstituted alkoxy groups for use in accordancewith the present invention include but are not limited to methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, and the like.

The terms “siloxy” and “silyloxy” refer to silicon substituted oxygengroups. The silicon-containing portion of the siloxy group may besubstituted or unsubstituted. Representative siloxy groups for use inaccordance with the present invention include but are not limited totrimethylsilyloxy (—OSi(CH₃)₃), triethylsilyloxy (—OSi(CH₂CH₃)₃),triisopropylsiloxy (—OSi(i-Pr)₃), t-butyldimethylsilyloxy(—OSi(t-Bu)(CH₃)₂), and the like.

The term “alkynyl” refers to a substituted or unsubstituted, straight,branched or cyclic unsaturated hydrocarbon chain containing at least onetriple bond and, preferably, from 2 to 20 carbon atoms.

The term “amino” refers to an unsubstituted or substituted amino (—NH₂)group. The amine may be primary (—NH₂), secondary (—NHR^(a)) or tertiary(—NR^(a)R^(b), wherein R^(a) and R^(b) are the same or different).Representative substituted amino groups for use in accordance with thepresent invention include but are not limited to methylamino,dimethylamino, ethylamino, diethylamino, 2-propylamino, 1-propylamino,di(n-propyl)amino, di(iso-propyl)amino, methyl-n-propylamino,t-butylamino, and the like.

The term “halogen” refers to fluorine, chlorine, iodine or bromine.

The term “heterocyclic” refers to a saturated, partially unsaturated, oraromatic ring system containing from 3 to 20, preferably 4 to 8, carbonatoms, and at least one, preferably 1 to 3, heteroatoms. The ring mayoptionally be substituted with one or more substituents. Moreover, thering may be mono-, bi- or polycyclic. Preferred heteroatoms forinclusion in the ring include but are not limited to nitrogen, oxygen,and sulfur. Representative heterocyclic groups for use in accordancewith the present invention include but are not limited to acridine,benzathiazoline, benzimidazole, benzofuran, benzothiapene, benzthiazole,benzothiophenyl, carbazole, cinnoline, furan, imidazole, 1H-indazole,indole, isoindole, isoquinoline, isothiazole, morpholine, oxazole (i.e.1,2,3-oxadiazole), phenazine, phenothiazine, phenoxazine, phthalazine,piperazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, thiazole,1,3,4-thiadiazole, thiophene, 1,3,5-triazines, triazole (i.e.1,2,3-triazole), and the like.

The term “reactant” refers to a functional group that will react with asecond functional group to form at least one bond.

The term “substituted” refers to the optional attachment of one or moresubstituents onto a backbone structure (e.g., an alkyl group, an alkenylgroup, etc.). Representative substituents for use in accordance with thepresent invention include but are not limited to hydroxyl, amino (—NH₂,—NHR^(a), —NR^(a),R^(b)), oxy (—O—), carbonyl (—CO—), thiol, alkyl,alkenyl, alkynyl, alkoxy, halo, nitrile, nitro, aryl and heterocyclylgroups. These substituents can optionally be further substituted with1-3 substituents. Examples of substituted substituents includecarboxamide, alkylmercapto, alkylsulphonyl, alkylamino, dialkylamino,carboxylate, alkoxycarbonyl, alkylaryl, aralkyl, alkylheterocyclyl,heterocyclylaryl, haloalkyl, and the like. The substituent should notsubstantially interfere chemically with the reaction of the invention(e.g., cross react with reactants, terminate the reaction or the like).When necessary, protecting groups may used to protect functionalsubstituents, as is well known in the art (see: Protective Groups inOrganic Synthesis, 3^(rd) Edition by Theodora W. Greene and Peter G. M.Wuts, John Wiley & Sons, Inc., New York, 1999).

Hydrogen-Bond Promoted Acceleration of HDA Reactions

A variety of spiro-fused dihydropyrans have been synthesized in goodyields using the new procedure, which represents an attractive andoperationally simple alternative to conventional, Lewis acid catalysis.A representative and non-limiting example of a HDA reaction embodyingfeatures of the present invention is shown in the following equation:

While investigating the solvent effect on the HDA reaction betweenaldehydes and 1-amino-3-siloxybutadiene, a surprisingly and unexpectedlyhigher reaction rate in chloroform was observed as compared to otherorganic solvents that are not capable of participating in hydrogenbonding (e.g., aprotic organic solvents). To more precisely assess thesolvent effect, the rate of the HDA reaction between diene 1 andp-anisaldehyde 2 was examined in several different solvents, as shown inTable 1. It is clear from the data in Table 1 that the rate differencesdo not correlate with the dielectric constant of the solvent: thereaction in chloroform was 10 times faster than in the more polarsolvent acetonitrile. Moreover, the higher rate in chloroform cannot beexplained by merely invoking catalysis from trace amounts of acid thatmight be present in the chloroform, since the same rate was observedeven after rigorous purification of the solvent. Furthermore, theaddition of triethylamine or a catalytic amount of HCl did not affectthe rate one way or another (it should be noted, however, that even ifthere were a trace amount of acid in the solvent, it would beneutralized by the basic nitrogen in the cycloadduct).

TABLE 1 Rates of HDA reactions in different solvents

dielectric rate constant entry solvent constant^(a) (k)^(b) relativerate 1 THF-d₈ 7.6 1.0*10⁻⁵ 1 2 benzene-d₆ 2.3 1.3*10⁻⁵ 1.3 3acetonitrile-d₃ 37.5 3.0*10⁻⁵ 3.0 4 chloroform-d 4.8 3.0*10⁻⁴ 30 5t-butanol-d₁₀ 10.9 2.8*10⁻³ 280 6 i-propanol-d₈ 18.3 6.3*10⁻³ 630^(a)For the corresponding undeuterated solvent, at 25° C. ± 5°.^(b)Kinetics measured by NMR integration using internal standard.

Without wishing to be bound by a particular theory or to in any waylimit the scope of the appended claims or their equivalents, it ispresently believed that the increased reaction rate in chloroform arisesfrom a C—H—O hydrogen bond between chloroform and the carbonyl oxygen,which would render the carbonyl group a stronger hetero-dienophile, asshown in FIG. 1 of U.S. Pat. No. 7,230,125. The rate of the HDA reactionin deuteriochloroform was the same, within experimental error, as thatin chloroform.

As the data in Table 1 above show, the cycloadditions are accelerated toa much greater extent in hydrogen bonding solvents, in which the OHgroup may be expected to form a strong hydrogen bond to the aldehydeoxygen. Thus, the HDA reaction of 1 and anisaldehyde is 630 times fasterin deuterated isopropanol than in deuterated THF, which corresponds to aΔΔG^(‡) of −3.77 kcal/mol.

Surprisingly and unexpectedly, the activation provided by hydrogenbonding solvents is sufficient to enable even simple ketones, whichaccording to conventional wisdom have generally been consideredunreactive, to undergo the HDA reaction. Initially, the HDA reaction ofcyclohexanone and diene 1 in chloroform was examined, as shown in Table2 below. Remarkably, although slow, the cycloaddition with thisunactivated ketone proceeded cleanly and gave, upon acetyl chloridemediated elimination of the amino group, the desired spiro-fuseddihydropyrone in 45% yield, along withE-4-(N,N-dimethylamino)-3-buten-2-one 5 (which may be obtained readilyfrom the hydrolysis or solvolysis of diene 1).

TABLE 2 Reactions of Cyclohexanone and 1 in Hydrogen-bonding Solvents.

entry solvent time (h) solvolysis (%)^(a) yield (%)^(c) 1 chloroform 4820-25 45 2 t-butanol 24 <5 71 3 i-propanol 3 10-15 60 4 ethanol 0.5~50^(b) 30 5 methanol 0.5 ~40^(b) 0 6 2-butanol 5 <5 78 ^(a)Percentageof hydrolysis was calculated by NMR integration. ^(b)A significantamount of other type of decomposition took place as well as hydrolysis.^(c)Yields refer to isolated, chromatographically purified products,except for entries 4 and 5, in which the yields are based on NMRintegration of cycloadduct.

As the data in Table 2 show, the cycloaddition was considerably fasterin hydrogen bonding solvents. The reaction went to completion in 1 dayin t-BuOH and, upon acetyl chloride workup, afforded the expected spiroproduct in 71% yield. Solvents with less shielded hydroxyl groups weremore effective at accelerating the HDA reaction.

The reaction went to completion in just 3h in i-propanol, but thedesired cycloadduct was accompanied by a significant amount (10-15%) ofthe solvolysis byproduct 5. Diene solvolysis predominated in ethanol andmethanol. The results indicate that although better hydrogen bondingalcohols promote faster reactions, they also solvolyze the diene. Theuse of 2-butanol (entry 6) provides a good compromise: the reaction wasreasonably fast and was accompanied by little of the undesiredsolvolysis byproduct.

This hydrogen bond promoted protocol represents the first general methodfor achieving the HDA reactions of unactivated ketones. A series ofreactions was carried out conveniently by mixing the diene and theketone in 2-butanol and letting the resulting solution stir at roomtemperature for the indicated time. The results are shown in Table 3below. The alcohol was removed in vacuo and replaced withdichloromethane. After cooling to −78° C., acetyl chloride was added,and the resulting solution subjected to an aqueous workup andchromatographic purification. This simple, one-pot procedure allows thepreparation of a variety of structurally novel spiro-dihydropyrones ingood yields.

TABLE 3 Cycloaddition Reactions of Diene 1 and Unactivated Ketones entryketone time^(a) product ratio yield (%)^(c)  1

  5 h

6a 78  2

  4 d

6b 35  3

5.5 h

6c 4.2:1 75  4

5.5 h

6d 2.8:1 74  5

5.5 h

6e   3:1 76  6^(b)

  8 h

6f 1.5:1 81  7

  3 h

6g 82  8

 19 h

6h 41  9

 30 h

6i 40 10

  6 h

6j  33^(d) 11

1.5 h

6k 77 ^(a)All reactions were carried out on an approximately 0.5 mmolscale in 0.5 mL 2-butanol using 2 equivalents of ketone. ^(b)The ketonewas dissolved in 0.2 mL of benzene. ^(c)Yields refer tochromatographically purified products. ^(d)An equal amount of theMukaiyama aldol side product was formed.

HDA reactions in accordance with the present invention are sensitive tosteric and electronic variations in the ketone. Whereas the reaction ofdiene 1 and cyclohexanone went to completion in just 5 hours, thereaction with 2-methylcyclohexanone was only ca. 50% complete after 4days (entry 2). By contrast, 2-methoxycyclohexanone was comparable inreactivity to cyclohexanone (entry 6). Evidently, the inductive effectof the methoxy group and its capacity to hydrogen bond override thesteric effect, as shown in FIG. 2 of U.S. Pat. No. 7,230,125.

Substituents at the 3 or 4 positions of cyclohexanone do not retard thereaction (entries 3-4). In general, six-membered ring ketones are moreeffective as heterodienophiles than other ketones (cf. entries 8-10).Finally, the HDA reaction of the hindered aldehyde, pivaldehyde, isgreatly accelerated in a hydrogen bonding solvent (entry 11). Thecorresponding reaction in chloroform was considerably slower andafforded the product in 54% product after 2 days (cf. Huang, Y.; Rawal,V. H. Org. Lett., 2000, 2, 3321).

The above-described results demonstrate the HDA reactions are greatlyaccelerated in hydrogen bonding solvents in accordance with the presentinvention. This activation protocol represents an attractive andoperationally simple alternative to conventional, Lewis acid catalysis.

Based on a joint consideration of the description herein and therepresentative procedures described below, the manner of making andusing the present invention will be abundantly clear to one of ordinaryskill in the art. For direction and guidance of a more general nature,the following representative literature materials are provided.

For further description of hydrogen-bond promoted acceleration of HDAreactions in accordance with the present invention, see: Huang, Y.;Viresh, V. H. J. Am. Chem. Soc., 2002, 124, 9662-9663, the entirecontents of which are incorporated herein by reference, except that inthe event of any inconsistent disclosure or definition from the presentapplication, the disclosure or definition herein shall be deemed toprevail.

For a summary of conventional HDA chemistry, see: (a) Tietze, L. F.;Kettschau, G. Top. Curr. Chem., 1997; 189, 1, and references therein.For earlier work, see: (b) Boger, D. L.; Weinreb, S. M. HeteroDiels-Alder Methodology in Organic Synthesis, Wasserman, H. H., Ed.;Academic Press: San Diego, Calif., 1987; Vol. 47.

For reviews on oxygen heterocycles, see: (a) Schmidt, R. R. Acc. Chem.Res., 1986, 19, 250. (b) Danishefsky, S. J.; DeNinno, M. P. Angew. Chem.Int. Ed. Engl., 1987, 15, 5. (c) Kametani, T.; Hibino, S. Adv.Heterocycl. Chem., 1987, 42, 245. (d) Bednarski, M. D.; Lyssikatos, J.P. In: Comprehensive Organic Synthesis; Trost, B. M., Heathcock, C. H.,Ed.; Pergamon Press: New York, 1991; Vol. 2, pp 661.

For a description of the special reaction conditions (e.g., hightemperature, high pressure, Lewis acid catalysis) required to performconventional HDA reactions, see: (a) Pindur, U.; Lutz, G.; Otto, C.Chemical Reviews, 1993, 93, 741. (b) Klärner, F.-G.; Wurche, F. J. Prak.Chem., 2000, 342, 609. (c) Kumar, A. Chem. Rev., 2001, 101, 1.

For examples of the difficulty of performing HDA reactions using simpleketones, compare inter alia: (a) Guay, V.; Brassard, P. Tetrahedron,1984, 40, 5039. (b) Schiess, P.; Eberle, M.; Huys-Francotte, M.; Wirz,J. Tetrahedron Lett., 1984, 25, 2201. (c) Midland, M. M.; Graham, R. S.J. Am. Chem. Soc., 1984, 106, 4294. (d) Daniewski, W. M.; Kubak, E.;Jurczak, J. J. Org. Chem., 1985, 50, 3963. (e) Rigby, J. H.; Wilson, J.A. Z. J. Org. Chem., 1987, 52, 34. (f) Chino, K.; Takata, T.; Endo, T.Synth. Commun., 1996, 26, 2145. (g) Brouard, C.; Pornet, J.; Miginiac,L. Synth. Commun., 1994, 24, 3047; (h) Huang, Y.; Rawal, V. H. Org.Lett., 2000, 2, 3321.

For a description of the HDA reaction between aldehydes and1-amino-3-siloxybuadiene, see: (a) Huang, Y.; Rawal, V. H. Org. Lett.,2000, 2, 3321. See also: (b) Kozmin, S. A.; Janey, J. M.; Rawal, V. H.J. Org. Chem., 1999, 64, 3039. (c) Kozmin, S. A.; Green, M. T.; Rawal,V. H. J. Org. Chem., 1999, 64, 8045. (d) Kozmin, S. A.; Rawal, V. H. J.Am. Chem. Soc., 1999, 121, 9562. (e) Huang, Y.; Iwama, T.; Rawal, V. H.J. Am. Chem. Soc., 2000, 122, 7843.

For information regarding the C—H—O hydrogen bond between chloroform andcarbonyl oxygens, see: (a) Green, R. D. Hydrogen Bonding by C—H Groups;Wiley: New York, 1974. (b) Steiner, T. New. J. Chem., 1998, 1099. (c)Kryachko, E. S.; Zeegers-Huyskens, Z. J. Phys. Chem. A., 2001, 105,7118, and citations therein.

For information relating to the well-established acceleration ofDiels-Alder reactions in water, see: (a) Breslow, R. Acc. Chem. Res.,1991, 24, 159. (b) Grieco, P. A. 133 Aldrichimica Acta, 1991, 24, 59.(c) Labineau, A.; Augé, J. Top. Curr. Chem., 1999, 206, 2.

For information relating to the hydrogen bond activation of dienophilesin standard Diels-Alder reactions, see: (a) Kelly, T. R.; Meghani, P.;Ekkundi, V. S. Tetrahedron Lett., 1990, 31, 3381. (b) Schuster, T.;Kurz, M.; Göbel, M. W. J. Org. Chem., 2000, 65, 1697. (c) Schreiner, P.R.; Wittkopp, A. Org. Lett., 2002, 4, 217.

Asymmetric Catalysis of Cycloaddition Reactions

Despite the central role of hydrogen bonding in determining thestructure and function of proteins, nucleic acids, and manysupramolecular assemblies, this weak interaction has hitherto beenrarely utilized as a force for promoting chemical reactions. However, ithas now been discovered that a chiral alcohol—through H-bonding—not onlyeffectively catalyzes an important family of cycloaddition reactions,but does so with exquisite levels of enantioselectivity.

Since most molecules of life (e.g., DNA, proteins, etc.) and manypharmaceutical drugs are chiral (i.e., not superimposable on theirmirror images or enantiomers), reactions that selectively produce oneenantiomer of a chiral compound are vitally important. Chemicalcatalysts that have been developed to address this need are generallybased on Lewis acidic metals. The above-described discovery that the HDAreactions of unactivated ketones and 1-amino-3-siloxy diene may besignificantly accelerated in hydrogen bonding solvents prompted aninvestigation of the use of chiral alcohols for the catalysis of suchcycloadditions.

Surprisingly and unexpectedly, the catalytic effect provided byhydrogen-bond donors can be extended to asymmetric or enantioselectivesynthesis. Throughout this description and in the appended claims, theterms “asymmetric” and “enantioselective” are used interchangeably.Presently preferred chemical reactions that may be used in accordancewith the present invention are reactions in which chiral hydrogen-bonddonors can produce products having an excess of one enantiomer inrelation to the other possible enantiomer. Representative chemicalreactions include but are not limited to: Diels-Alder reactions, dipolarcycloadditions, carbene additions, cyclopropanation, aziridination,additions of nucleophiles to carbonyl groups (e.g., by Grignardreagents, stannanes, silanes, organozincs, and other organometallics),addition of nucleophiles to alpha, beta-unsaturated carbonyls (e.g., byGrignard reagents, stannanes, silanes, organozincs, cuprates,organomaganese compounds, and other organometallics), nucleophilicaddition to imines, cyanohydrin formation, cyanoamine formation,reductions of ketones and imines, and the like.

Without wishing to be bound by a particular theory or to in any waylimit the scope of the appended claims or their equivalents, it ispresently believed that an enantioselective reaction occurs due tocoordination of a hetero-olefin, such as a carbonyl group or an iminegroup, to the chiral hydrogen-bond donor, such as an alcohol. Thiscoordination is presently believed to occur through hydrogen bondingand/or other non-bonding interactions and to hinder the approach of thereactant to one face of the hetero-olefin in relation to the other faceof the hetero-olefin. Consequently, the addition of the reactant takesplace selectively to one face of the hetero-olefin over the other face.Similarly, with alpha, beta-unsaturated carbonyl compounds and alpha,beta-unsaturated imine compounds, the coordination to the chiralhydrogen-bond donor is presently believed to selectively block thecarbonyl carbon (or the imine carbon) in addition to the alpha and betacarbons. The result is that reactants are presently believed toselectively react on one face of these planar groups over the other.Thus, the two faces of the hetero-olefin become prochiral. Suchselectively is also commonly referred to as enantiofacial selectivity.

In a presently preferred embodiment, highly enantioselective HDAreactions are catalyzed with chiral hydrogen-bond donors, includingalcohols. The resultant cycloadduct products are produced in good yieldswith extremely high optical purity. In addition, metal and Lewis acidfree hydrogen-bond donor catalysts are provided that offer advantagesover conventional metal catalyzed reactions. These benefits include butare not limited to lower cost, increased sensitivity, and increasedenvironmental friendliness. The extension of the above-describedhydrogen bond acceleration concept to asymmetric synthesis is furtherexplained below.

Asymmetric synthesis or enantioselective synthesis occurs when one oftwo possible enantiomeric products is preferentially formed from areaction. Enantiomeric excess (ee) is a measure of the preference forone enantiomer over the other. Thus, if R and S type enantiomers arepossible and a reaction produces more of the R enantiomer than the Senantiomer, the ee for the reaction will reflect the degree ofpreference for formation of the R enantiomer.

A hydrogen bond may form when a covalently bonded hydrogen atom is inclose proximity to a heteroatom. For example, if the hydrogen atomcovalently bonded to the oxygen atom of an alcohol comes in closecontact with the oxygen of a carbonyl group, a hydrogen bondinginteraction can occur between the hydrogen atom and the oxygen of thecarbonyl. The alcohol having the hydrogen atom covalently bonded to theoxygen serves as a hydrogen-bond donor. The carbonyl group serves as ahetero-olefin. If the carbonyl were to be further reacted with a dienein a Diels-Alder type reaction, the carbonyl would serve as ahetero-dienophile. Representative heteroatoms for participation in theformation of hydrogen bonds include but are not limited to oxygen,nitrogen, sulfur, fluorine, and chlorine.

Catalytic, enantioselective HDA reactions are an efficient method forthe construction of optically active six-membered heterocycles. In thesereactions, a diene, which includes two or more conjugated double bondsis reacted with a hetero-olefin. Hetero-olefins used in Diels-Alderreactions are often referred to as hetero-dienophiles or, moregenerally, dienophiles.

A typical, asymmetric catalyzed Diels-Alder reaction between a diene anda hetero-olefin (dienophile) is shown in Scheme 1 below:

Y represents O, S, or NR7. R1, R2, R3, R4, R5 and R6 each independentlyrepresents hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl,alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides,phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls,ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters,or —(CH₂)_(m)—R8. Any two or more of the substituents R1, R2, R3, R4, R5and R6 taken together may form a carboxylic or heterocyclic ring havingfrom 4 to 8 atoms in the ring structure. R8 represents an aryl, acycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is aninteger from 0 to 8. In certain embodiments, R1, R2, R3, and R4 arechosen such that the substrate has a plane of symmetry.

Exemplary dienophiles suitable for use in accordance with the presentinvention include but are not limited to aldehydes, ketones, esters,amides, carbonates, thioaldehydes, thioamides, thiocarbonates, lactones,lactams, thiolactones, thiolactams, imines, oximes, hydrazones,thionoesters, thioesters, dithioesters, thionolactones, dithiolactones,phosphorus ylides, thioketones, acid halides, anhydrides, iminium ions,nitroso-containing compounds, nitro-containing compounds, compoundscontaining a phosphorus-oxygen π-bond, and compounds containing aphosphorus-sulfur π-bond.

As noted above, conventional methods for catalyzing asymmetricDiels-Alder reactions typically involve the use of metals, such as Lewisacids. Examples of the conventional methodologies are shown in Schemes2-7 below.

Lewis acid catalysis has been extended to use chiral ligands forasymmetric induction. With a sterically demanding chiral ligand inproximity, the two pro-chiral faces of a carbonyl group can bedifferentiated. The change in hybridization of oxygen from sp² to sp³favors turnover of the precious chiral catalyst.

FIG. 3 of U.S. Pat. No. 7,230,125 shows a group of representativemetal-containing and Lewis acid catalysts that have been used for HDAreactions.

Hydrogen bonds may activate certain types of chemical reactions.However, too little reaction activation from the hydrogen bondinginteraction can be a limiting factor since the strength of a hydrogenbonding interaction is generally less than that of a Lewis acid.

As noted above, HDA reactions in accordance with the present inventionare greatly accelerated by solvents capable of hydrogen bonding. Forexample, as shown in Scheme 8 below, the reaction rate in 2-butanolwas >600 times faster than in benzene and THF. The rate differenceaccounts for more than a 3.5 kcal/mol activation energy drop at 25° C.Surprisingly and unexpectedly, good enantioselectivity is achieved whenan appropriate chiral alcohol is used.

The reaction between diene 1 and benzaldehyde 278 shown in Scheme 8above was used as a model for examining several chiral acidichydrogen-bond donors which have one acidic proton. These hydrogen-bonddonors are shown in FIG. 4 of U.S. Pat. No. 7,230,125. The reaction wascarried out using 2 equivalents of chiral hydrogen-bond donor. Underthese conditions, oxazolidinone 372 and benzoin 373 caused significantdiene decomposition, resulting in little product being isolated.Additionally, menthol 371 failed to provide decent activation. Thereaction was also very slow at low temperature (−78 to 0° C.). However,the product obtained from room temperature reaction was isolated in pooryields and with a low enantiomeric excess of only about 3%. Althoughlow, a slight enantioselectivity was thus demonstrated. Accordingly,these conditions were further optimized.

Without wishing to be bound by a particular theory or to in any waylimit the scope of the appended claims or their equivalents, it ispresently believed that 1,2-diols potentially have the benefit offorming complexes of type A or type B shown in FIG. 5 of U.S. Pat. No.7,230,125. In model A, intramolecular hydrogen-bonding of the catalystmay provide additional activation. In model B, a possibledi-hydrogen-bonding interaction of the catalyst with the aldehyde couldpotentially double the degree of activation provided.

Under one set of conditions, (R)-BINOL 378 and L-tartaric acid dimethylester 376 resulted in diene decomposition. It is now believed that thesealcohols may be too acidic to be compatible with diene 1. Under similarconditions, (R,R)-hydrobenzoin 375 did not significantly catalyze theHDA reaction, and the diene was slowly hydrolyzed. (R,R)-2,3-Butanediol374 and D-mannitol diacetonide 377 did catalyze the HDA reaction, butonly to a slight degree (ee value of 3% and 6%, respectively, weredetermined by chiral HPLC). FIG. 6 of U.S. Pat. No. 7,230,125 shows aseries of chiral diols tested during this stage of the development.Further optimization of the conditions for catalyzing HDA reactions withthese alcohols was performed as described below.

A class of chiral diols known as TADDOLs was next examined in connectionwith the HDA reaction between diene 1 and benzaldehyde. TADDOL is anabbreviation forα,α,α′,α′-tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol, shown inFIG. 7 of U.S. Pat. No. 7,230,125, which include a series of acetals andketals of 1,1,4,4-tetraarylthreitols (see, for example: Seebach, D.;Beck, A. K.; Heckel, A. Angew. Chem. Int. Ed., 2001, 40, 92-138).

Surprisingly and unexpectedly, TADDOL type diols provided excellentresults, as shown in Scheme 9 below. TADDOL 379 was moderately solublein toluene at room temperature. Upon addition of 2 equivalents ofbenzaldehyde, the opaque mixture turned clear immediately and remainedclear even at −78° C. The increased solubility of TADDOL in the presenceof benzaldehyde suggested a strong interaction between the diol and thecarbonyl. A smooth HDA reaction occurred upon addition of1-amino-3-siloxybutadiene 1 at −78° C. Crude ¹H NMR indicated that asingle diastereomer was being formed, tentatively believed to be an endoisomer. Acetyl chloride workup afforded dihydropyran 261 in 47% yield.The product was separated on a chiral HPLC column (Diacel OD-H) and theee was determined to be 37%.

Scheme 9 clearly demonstrates the concept of asymmetric catalysis by achiral hydrogen bond donor. A sub-stoichiometric amount of chiral diolwas used, and good catalyst turnover was achieved.

Two additional TADDOLs, as shown in Scheme 10 below, were purchased fromAldrich Chemical Co. (Milwaukee, Wis.) and used to catalyze the HDAreaction between 1 and 249. 2-Naphthyl TADDOL 380 resulted in moreundesirable products being formed than with TADDOL 379. A NMR calculatedyield for the reaction was ˜30%. However, the product had anenantiomeric excess of 68%, demonstrating the significantenantioselectivity of the reaction. Surprisingly and unexpectedly,1-naphthyl TADDOL 381 afforded a very clean reaction with few sideproducts and the desired cycloadduct product was isolated in 63% yield.Remarkably, the ee of the cycloadduct approached nearly 100%, giving agreater than 200:1 enantiomeric ratio in the chiral HPLC spectrum.

The catalyst loading was further lowered to 20 mmol %. Nonetheless, theHDA reaction was almost complete after 48 hours at −78° C. and,remarkably, Dihydropyran 261 was separated in a 70% yield and >99% eeafter silica gel chromatography.

TADDOL is readily prepared from tartaric acid diesters through aBarbier-Wieland reaction sequence: addition of excess aryl Grignardreagent to ester affords the corresponding diarylcarbinol functionalityof TADDOL. The tertiary alcohols allow convenient derivatization in asense of combinatorial optimization. Heteroatoms including but notlimited to halogens, O, N, P, S, Si, and B can be easily incorporatedinto the TADDOL framework. Other small chiral molecules (as opposed totartrates) can also be introduced for asymmetry. Thousands of versatileligands and catalysts bearing the TADDOL skeleton have been prepared andutilized in asymmetric reactions, as shown in FIG. 8 of U.S. Pat. No.7,230,125.

An advantageous property of TADDOLs is their tendency to formcrystalline solids. There are roughly 120 crystal structures ofcompounds of the type shown in FIG. 8 of U.S. Pat. No. 7,230,125. TheTADDOL skeleton adopts a nearly perfect staggered, C₂-symmetricconformation, as shown in FIG. 9 of U.S. Pat. No. 7,230,125. A vastnumber of reactions in which TADDOL and TADDOL derivatives are used toactivate hetero-olefins for further reaction are contemplated inaccordance with the present invention particularly vis-á-vis Diels-Alderreactions in which a hetero-olefin serves as a dienophile.

Without wishing to be bound by a particular theory or to in any waylimit the scope of the appended claims or their equivalents, it ispresently believed that the chirality from the stereogenic centers onthe dioxolane ring was amplified through a propeller-shape structure.Two of the aryl groups are presently believed to orient axially, whilethe other two aryl groups are presently believed to orient equatorially.At least one of the alcoholic protons is presently believed toparticipate in an intramolecular hydrogen bond, leaving the otheralcoholic proton free for intermolecular interaction with thehetero-olefin.

Without wishing to be bound by a particular theory or to in any waylimit the scope of the appended claims or their equivalents, it isfurther presently believed that hydrogen bonding plays a very importantrole in TADDOL based asymmetric synthesis. The formation of an inclusioncomplex may be energetically driven by hydrogen bonding between TADDOLand the electronegative atoms in the substrates. The success in theresolution of racemic mixtures clearly shows that TADDOLs are able tobind to one enantiomer from a racemic mixture with a selectivity greaterthan 100:1. Thus, it is presently believed that TADDOLs may also providesignificant activation of carbonyls through a hydrogen bondinginteraction.

All manner of aldehydes and ketones are contemplated for use ashetero-olefins for use in accordance with HDA reactions embodyingfeatures of the present invention. As shown by the data in Table 4below, both aromatic and aliphatic aldehydes participated in HDAreactions at low temperature in the presence of 20 mol % of1-naphthyl-TADDOL. Dihydropyrans 4 were isolated in 50-97% yields withexcellent ee.

TABLE 4 Highly Enantioselective HDA Reactions Catalyzed by 1-NaphthylTADDOL 381

Entry R Temp (° C.) Time (h) Yield (%) ee (%)  1 Ph −78 48 70 98  24-MeO—C₆H₄ −40 24 68 94  3 2-O₂NC₆H₄ −20 24 69 80  4 4-F₃C—C₆H₄ −78 4868 95  5 1-naphthyl −78 48 69 99  6 4-MeC₆H₄ −78 48 68 98  7* 4-ClC₆H₄−78 48 60 85  8 C₆H₅CH₂OCH₂ −78 48 40 97  9 C₆H₁₁ −40 24 64 87 10PhCH₂CH₂ −40 48 73 71 11 2-naphthyl −40 24 97 94 12 2-furyl −78 48 67 9213 propyl −40 10 71 88 14 m-Br-phenyl −78 24 61 97 15 trans-styrenyl −4520 52 95 *A 1:1 mixture of toluene and methylene chloride was used todissolve the substrate at −78° C.

A suspension of 0.25 mmol of (R,R)-1-naphthyl TADDOL (381, purchasedfrom Aldrich) in toluene at −78° C. became homogeneous upon addition of1.0 mmol of benzaldehyde. Subsequent addition of 0.5 mmol of1-amino-3-siloxybutadiene 1 caused a smooth HDA reaction to take place.Analysis of the crude reaction mixture by ¹H NMR indicated the formationof the expected cycloadduct as a single diastereomer (R═C₆H₅),tentatively assigned as endo. Upon treatment with acetyl chloride (1.0mmol, −78° C.), the cycloadduct was converted to a dihydropyrone(R═C₆H₅), which was isolated in 63% overall yield. Chiral HPLC analysisshowed that the reaction had produced the S-enantiomer preferentiallyover the R, with >99:1 enantiomer ratio (er). The reaction was equallyeffective using only 20 mol % of catalyst 2 (70% yield, >99:1 er). Thereaction rate acceleration provided by TADDOL 381 is considerable: inits absence, no reaction took place under otherwise identicalconditions. The full hydrogen bonding capability of 381 is presentlybelieved to facilitate catalysis. The dimethylether derivative of 381was ineffective as a catalyst and the monomethyl ether gave poorcatalysis.

This metal-free asymmetric catalysis method, which does not involve acovalent connection between the catalyst and the reactant (see: Dalko,P. I.; Moisan, L. Angew. Chem. Int. Ed., 2001, 40, 3726-3748) is usefulfor the cycloadditions between 1 and a range of aldehydes.

Aromatic aldehydes were particularly effective as dienophiles in thesecatalyzed HDA reactions. The resultant dihydropyrone products wereobtained in uniformly high enantiomer ratios. However, the conditionswere not optimized. The reaction required slightly higher temperatureand ee dropped to 88% for n-butyraldehyde. Nevertheless, thismethodology represents enantioselective HDA reactions catalyzed bychiral hydrogen-bond donors (organocatalysts). The successful use ofaliphatic and α,β-unsaturated aldehydes (e.g., entry 15) in thesereactions is noteworthy.

Based on a joint consideration of the description herein and therepresentative procedures described below, the manner of making andusing the present invention will be abundantly clear to one of ordinaryskill in the art. For further description of asymmetric catalysis ofcycloaddition reactions in accordance with the present invention, see:Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature, 2003, 424,146, the entire contents of which are incorporated herein by reference,except that in the event of any inconsistent disclosure or definitionfrom the present application, the disclosure or definition herein shallbe deemed to prevail.

Asymmetric Catalysis of Diels-Alder Reactions with α,β-UnsaturatedCarbonyl Dienophiles

It has further been discovered that the above-described catalysts arenot limited to the catalysis of HDA reactions but rather are also usefulfor the catalysis of traditional (i.e., non-hetero) Diels-Aldercycloadditions with dienophiles including but not limited toα,β-unsaturated carbonyl compounds. A presently preferred class ofdienophiles for use in accordance with this aspect of the presentinvention is α,β-unsaturated aldehydes, such as the acrolein class ofcompounds.

Examples of TADDOL-catalyzed Diels-Alder reactions of 1-amino-3-siloxydienes with acroleins are shown in Table 5 below.

TABLE 5 TADDOL Catalyzed Diels-Alder Reactions of 1-Amino-3-SiloxyDienes with Acroleins

yield of 504 yield of 503 Entry R (%) (%) ee of 503 (%) 1 H ^(a) 81 81 2Me 87 85 93 3 Et 83 81 91 4 ^(i)Pr 87 83 93 5 Bn 84 80 95 6 CH₂CH₂OTBS81 81 90 ^(a)Product was unstable: rapid decomposition upon removal ofsolvent at rt

It should be noted that while 1-amino-3-siloxybutadiene 1 is a presentlypreferred diene for use in accordance with the present invention, otherless electron rich dienes, such as 1-amino dienes, also have been usedand shown to work. Examples of the reaction between a 1-amino-diene withacroleins are shown in Table 6 below.

TABLE 6 TADDOL Catalyzed Diels-Alder Reactions of 1-Amino-Dienes withAcroleins

yield of 506 yield of 507 Entry R (%) (%) ee of 507 (%) 1 H 77 79 89 2Me 81 83 93 3 Et 76 79 91 4 Bn — 51 92 6 CH₂CH₂OTBS —  67^(a) 87^(a)Contaminated with ca. 15% of a byproduct derived from 507.

In view of the very promising results of the 1-napthyl TADDOL-catalyzedDiels-Alder reaction of aminosiloxy diene 505, it is of interest tounderstand the mechanism and reactivity profile of this novel process.The gross structural features of the TADDOL class of ligands have beenstudied. At present, there are over 50 X-ray crystal structures ofTADDOLs with a hydrogen bond acceptor (typically simple aliphaticalcohols, such as MeOH). All of the TADDOLs display C₂ symmetry with apropeller-type arrangement of the aryl rings. Unfortunately, there areno X-ray crystal structures of TADDOLs with an aldehyde. Results to datehave suggested that the solvent plays an important role in the actualcrystallization of the complex.

In the absence of structural data, molecular modeling studies have beenconducted. A presently preferred model that accurately explains theactivation of the dienophile and correctly predicts the absolutestereochemical outcome for the reaction of both aliphatic and aromaticaldehydes is shown in FIG. 9 of U.S. Pat. No. 7,230,125.

Without wishing to be bound by a particular theory or to in any waylimit the scope of the appended claims or their equivalents, it ispresently believed that the dienophile (benzaldehyde is shown) isactivated through a two-point interaction. First, an intermolecularhydrogen bond between the hydrogen of one of the hydroxyl groups and thecarbonyl provides the necessary lowering of the LUMO energy through aLewis acid like mechanism. Second, the carbonyl double bond is locatedin proximity to the π system of one of the 1-napthyl rings and isstabilized through a π-π interaction, wherein one component is electronrich and the other component is electron poor.

Based on the above-described model, the aryl or alkyl substituent ispositioned away from the naphthalene ring. This model suggests that theSi face of the aldehyde is accessible to the aminosiloxy diene andcorrectly predicts the absolute configuration of the obtainedcycloadduct.

As is well known in the art, an elucidation of the true mechanism of thecatalyzed reaction may be investigated by analyzing the kinetics andthermodynamics of the reaction. Rate constants and the orders of thereactants may be obtained by carefully monitoring the progress of thereaction by integration of the reactants and product signals in highfield proton NMR experiments. Data taken at different reactantconcentrations will determine the order of each reactant and the overallorder of the reaction, thereby determining the overall rate law for thisreaction. A similar process of monitoring the course of the reactionover a range of temperatures using variable temperature high fieldproton NMR would provide data to determine critical thermodynamicparameters (E^(a), ΔH, and αG) of the reaction. Lastly, the possibilityof aggregate or other complex behavior of the catalyst during the courseof the reaction could be investigated through the presence of anon-linear relationship between the enantiomeric purity of the catalystand that of the product (for example, see: Blackmond, D. G. “Descriptionof the condition for asymmetric amplification in autocatalyticreactions,” Adv. Synth. Catal., 2002, 344, 156-158; Blackmond, D. G.“Kinetic Aspects of Nonlinear Effects in Asymmetric Catalysis,” Acc.Chem. Res., 2000, 33, 402-411; and Boim, C. “Non-linear effects inenantioselective synthesis: asymmetric amplification,” AdvancedAsymmetric Synthesis, 1996, 9-26).

Tuning of the electronic and steric properties of TADDOLs is guidedaccording to the above-described model for rationalizing the outcome ofthe 1-naphthyl TADDOL catalyzed HDA reactions. As noted above, thismodel highlights the importance of π-stacking in the TADDOL-aldehydecomplex. This, in turn, suggests that fine tuning the electronic (andpossibly steric) properties of the 1-naphthyl ring system would bedesirable for the development of even more highly enantioselectivecatalysts.

By way of example, preferred modifications of the TADDOL skeletoninclude introducing electron-rich and/or electron-poor substituents,such as the 1-halo-naphthyl derivatives shown in FIG. 10 of U.S. Pat.No. 7,230,125. These may be synthesized according to well-establishedprocedures and converted into the corresponding TADDOL ligands. Allmanner of chemical transformations known in the art—including but notlimited to those described in treatises such as Comprehensive OrganicTransformations, 2^(nd) Edition by Richard C. Larock (Wiley-VCH, NewYork, 1999) and March's Advanced Organic Chemistry, 5^(th) Edition byMichael B. Smith and Jerry March (John Wiley & Sons, Inc., 2001), andreferences cited therein, are contemplated for use in accordance withthe present invention. The tuning of the electronic properties of theα-ring (i.e., the ring directly connected to the remaining part ofTADDOL) (FIG. 10 of U.S. Pat. No. 7,230,125, 60) and/or the β-ring ofthe naphthyl system (61) would provide an indication of which of the twoπ systems is more important for increasing the enantioselectivity of theHDA reaction. To probe the importance of π stacking, fully saturatedversions (e.g., a cyclohexane based motif) and partially saturated(e.g., cyclohexene-based motif) versions of TADDOL may be synthesizedand tested.

Other preferred modifications to the TADDOL skeleton include structuralmodifications of the aryl rings. Strategic placement of methyl (or evenbulkier aliphatic groups) around the 1-naphthyl ring system 62 mayresult in a better overall catalyst. Alternatively, it might be possibleto simply use a phenyl-based catalyst appropriately substituted withaliphatic groups (63, 64). Two other derivatives that are presentlypreferred include the 1-anthracenyl and phenanthrenyl variants of TADDOL65 and 66. As used herein, the term “derivative” is to be understood asreferring to a chemical compound made from a parent compound by one ormore chemical reactions.

Further preferred modifications to the TADDOL skeleton include changingthe structure of the acetonide region of the molecule, shown in FIG. 11of U.S. Pat. No. 7,230,125, which is presently believed to have aneffect on the selectivity and efficiency of the catalysts.

Other catalysts in accordance with the present invention are based onchiral 1,2-diols, 1,4-diols, 1,3-diols, and 1,6-diols (e.g., binap-typecompounds). C₂-Symmetrical diols with the possibility of π-πinteractions are presently preferred. Other chiral diols embodyingfeatures of the present invention include the BINOL ligands and theirderivatives and other tartrate-derived 1,4-diols. In addition, chiralamino alcohols (or di- and tripeptides) are also presently preferredtemplates for hydrogen bond donors.

In summary, alcohols have been discovered that promote HDA reactions of1-amino-3-siloxybutadiene at much higher rates than other solvents.Hydrogen bonding is believed to be a primary reason for this unusualacceleration. Unactivated, simple ketones reacted readily with1-amino-3-siloxydienes in 2-butanol to give dihydropyrans having aquaternary carbon. Moreover, it has been discovered that thehydrogen-bond strategy may be successfully extended to asymmetriccatalysis. Successful hydrogen-bond catalyzed asymmetric reactions weredeveloped using chiral TADDOLs. The reactions proceeded at lowtemperature, with good yields and with excellent ee demonstrating thathydrogen bonding by a simple chiral alcohol to a carbonyl group mayaccomplish what previously had been considered the domain of chiralmetal-based Lewis acids. Catalytic amounts of chiral TADDOL were used todemonstrate the catalytic nature of the reaction. Furthermore, it hasbeen discovered that the TADDOL-type catalysts are not limited to thecatalysis of HDA reactions but rather are also useful for the catalysisof traditional (i.e., non-hetero) Diels-Alder cycloadditions withdienophiles such as α,β-unsaturated carbonyl compounds.

Asymmetric Catalysis of the Alkynylation of Aldehydes

It has further been discovered that the above-described catalysts arenot limited to the catalysis of cycloaddition reactions but are alsouseful for the catalysis of a variety of non-cycloaddition asymmetricreactions including but not limited to 1,2-addition reactions tocarbonyl compounds. A presently preferred 1,2-addition reaction for usein accordance with the present invention is the alkynylation ofaldehydes.

A presently preferred class of catalysts for performing asymmetricalkynylations of aldehydes in accordance with the present invention isthe TADDOL family of catalysts described above. Table 7 below shows datafor enantioselective alkynylation of aldehydes in accordance with thepresent invention.

TABLE 7 Enantioselective Alkynylation of Aldehydes

temp ee Equiv. of TADDOL solvent (° C.) yield (%) (%) 0.1 PhCH₃ rt 76 130.2 PhCH₃ rt 77 15 0.1 PhCH₃ −10 79 16 0.1 THF rt <40% — conversion

The following examples and representative procedures illustrate featuresin accordance with the present invention, and are provided solely by wayof illustration. They are not intended to limit the scope of theappended claims or their equivalents.

EXAMPLES

General Procedure for HDA Reactions Shown in Table 3

General: All reactions were carried out under a nitrogen atmosphere.Common solvents were purified before use. Tetrahydrofuran (THF) anddiethyl ether (Et₂O) were purified by distillation frompotassium-benzophenone ketyl. Other solvents were freshly distilled fromcalcium hydride prior to use. All commercial chemicals were reagentgrade and purified as necessary. KHMDS was used from newly opened 100 mLbottles, purchased from Aldrich, Inc. Reactions were monitored by thinlayer chromatography (TLC) using 250 mm Whatman precoated silica gelplates. Flash column chromatography was performed over Fisher or EMScience Laboratories silica gel (230-400 mesh). Melting points weremeasured on a Thomas Hoover capillary melting point apparatus and areuncorrected. Carbon and proton NMR spectra were recorded on BrukerDRX-500 spectrometer. ¹H NMR chemical shifts are reported as δ values(ppm) relative to internal tetramethylsilane and splitting patterns aredesignated as: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet,br=broad. Coupling constants are given in hertz (Hz).

Materials:N,N-dimethyl-1-amino-3-^(t)Butyldimethylsilyloxy-1,3-butadiene wasprepared according to our published procedures and redistilled prior touse. For example, see: (a) Kozmin, S. A.; Janey, J. M.; Rawal. V. H. J.Org. Chem. 1999, 64, 3039 and (b) Kozmin, S. A.; He, S.; Rawal, V. H.Org. Synth. 2000, 78, 152-159; ibid, p 160. Ketones were purchased fromAldrich, Inc. and freshly distilled or recrystallized prior to use.Acetyl chloride was purchased from Aldrich, Inc. and freshly distilledfrom N,N-dimethylaniline prior to use. Anhydrous grade 2-butanol waspurchased from Aldrich, Inc. and freshly distilled from calcium hydrideprior to use.

Procedure: To a 10 mL oven-dried flask was added (1.0 mmol, 2.0 eq.)ketone and 0.5 mL 2-butanol. Diene 1 (114 mg, 0.5 mmol, 1.0 eq.) wasthen added slowly at room temperature. The reaction mixture was stirreduntil diene was fully consumed (NMR). The solvent was removed in vacuoand the residue was redissolved in 4 mL of ether. The pale yellowsolution was cooled to −78° C., and 43 μL acetyl chloride (0.6 mmol, 1.2eq.) in 1 mL ether was added slowly. The mixture was stirred at −78° C.for ca. 10 min and quenched with 5 mL saturated sodium bicarbonatesolution. The organic layer was separated, and the aqueous phaseextracted twice with ether. The combined organic phase was dried withmagnesium sulfate, filtered, and concentrated. The yellow residue waspurified by flash chromatography to afford the desiredspirodihydropyrone compounds 6.

6a (1-oxaspiro[5,5]undec-2-en-4-one): Flash chromatography on silica gel(10% ethylacetate/hexane) gave 65 mg (78%) of 6a, a light yellow oil. ¹HNMR (500 MHz, CDCl₃, ppm) δ 7.25 (d, J=6 Hz, 1 H), 5.35 (d, J=6 Hz, 1H), 2.50 (s, 2H), 2.02 (br d, J=13 Hz, 2 H), 1.50 (m, 8 H). ¹³C NMR (125MHz, CDCl₃, ppm) δ 192.4, 161.1, 105.6, 82.3, 47.2, 34.2, 25.0, 21.4.FIGS. 12 and 13 of U.S. Pat. No. 7,230,125 show the ¹H NMR spectrum and¹³C NMR spectrum, respectively, of spiro-dihydropyrone 6a.

6b (6-methyl-1-oxaspiro[5,5]undec-2-en-4-one): Flash column on silicagel (25% ether/hexane) gave 32 mg (35%) of 6d, a light yellow oil. NMRshowed that the product was a mixture of diastereomers (3.3:1). FIGS. 14and 15 of U.S. Pat. No. 7,230,125 show the ¹H NMR spectrum and ¹³C NMRspectrum, respectively, of spiro-dihydropyrone 6b.

Major isomer: ¹H NMR (400 MHz, CDCl₃, ppm) δ 7.27 (d, J=6 Hz, 1 H), 5.34(d, J=6 Hz, 1 H), 2.98 (d, J=16 Hz, 1H), 2.19 (br d, J=15 Hz, 1H), 2.10(d, J=16 Hz, 1H), 1.40 (m, 8 H), 1.00 (d, J=6 Hz, 3H) ¹³C NMR (100 MHz,CDCl₃, ppm) δ 193.0, 161.3, 105.4, 82.9, 44.9, 38.9, 31.8, 29.6, 25.1,21.4, 15.8.

Minor isomer: ¹H NMR (400 MHz, CDCl₃, ppm) δ 7.26 (d, J=6 Hz, 1 H), 5.33(d, J=6 Hz, 1 H), 2.66 (d, J=16 Hz, 1H), 2.45 (br d, J=15 Hz, 1H), 1.95(d, J=16 Hz, 1H), 1.40 (m, 8 H), 1.00 (d, J=6 Hz, 3H) ¹³C NMR (100 MHz,CDCl₃, ppm) δ 192.5, 161.5, 105.2, 77.3, 39.7, 39.2, 31.3, 30.1, 23.5,22.2, 15.5.

6c (7-methyl-1-oxaspiro[5,5]undec-2-en-4-one): Flash column on silicagel (7% and 12% ethylacetate/hexane) gave 68 mg (75%) of 6d as a paleyellow oil. NMR showed that the product was a 4.2:1 mixture ofdiastereomers. FIGS. 16 and 17 of U.S. Pat. No. 7,230,125 show the ¹HNMR spectrum and ¹³C NMR spectrum, respectively, of spiro-dihydropyrone6c.

Major isomer: ¹H NMR (500 MHz, CDCl₃, ppm) δ 7.24 (d, J=6 Hz, 1 H), 5.36(d, J=6 Hz, 1 H), 2.46 (s, 2H), 2.15 (m, 2 H), 1.76 (m, 2 H), 1.62 (m, 2H), 1.20 (m, 1 H), 0.90 (d, J=6 Hz, 3 H), 0.89 (m, 2 H). ¹³C NMR (125MHz, CDCl₃, ppm) δ 192.5, 161.1, 105.7, 82.4, 48.5, 42.6, 33.8, 33.5,27.3, 22.2, 20.9.

Minor isomer: ¹H NMR (500 MHz, CDCl₃, ppm) δ 7.23 (d, J=6 Hz, 1 H), 5.34(d, J=6 Hz, 1 H), 2.66 (s, 2 H), 2.05 (m, 2 H), 1.50 (m, 5 H), 0.93 (d,J=6 Hz, 3 H), 0.91 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃, ppm) δ 192.2,161.5, 105.4, 84.2, 43.7, 43.0, 34.4, 34.0, 29.0, 22.2, 22.0.

6d (8-methyl-1-oxaspiro[5,5]undec-2-en-4-one): Flash column on silicagel (8% and 12% ethylacetate/hexane) gave 67 mg (74%) of 6d as lightyellow oil. NMR showed that the product was a 2.8:1 mixture ofdiastereomers. FIGS. 18 and 19 of U.S. Pat. No. 7,230,125 show the ¹HNMR spectrum and ¹³C NMR spectrum, respectively, of spiro-dihydropyrone6d.

Major isomer: ¹H NMR (500 MHz, CDCl₃, ppm) δ 7.25 (d, J=6 Hz, 1 H), 5.36(d, J=6 Hz, 1 H), 2.45 (s, 2 H), 2.18 (m, 2 H), 1.70 (m, 1 H), 1.54 (m,2 H), 1.31 (m, 4 H), 0.94 (d, J=6 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃,ppm) δ 192.5, 161.0, 105.7, 81.4, 48.2, 33.9, 31.4, 29.5, 22.1.

Minor isomer: ¹H NMR (500 MHz, CDCl₃, ppm) δ 7.24 (d, J=6 Hz, 1 H), 5.34(d, J=6 Hz, 1 H), 2.64 (s, 2 H), 2.02 (m, 2 H), 1.40 (m, 7 H), 0.93 (d,J=6 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃, ppm) δ 192.2, 161.5, 105.5, 83.6,43.8, 33.7, 31.1, 30.3, 20.9.

6e (8-^(t)Butyl-1-oxaspiro[5,5]undec-2-en-4-one): Flash column on silicagel (5% and 10% ethylacetate/hexane) gave 85 mg (74%) of product 6e aswhite solid. NMR showed that the product was a mixture of diastereomers(3:1). FIGS. 20 and 21 of U.S. Pat. No. 7,230,125 show the ¹H NMRspectrum and ¹³C NMR spectrum, respectively, of spiro-dihydropyrone 6e.

Major isomer: ¹H NMR (500 MHz, CDCl₃, ppm) δ 7.26 (d, J=6 Hz, 1 H), 5.37(d, J=6 Hz, 1 H), 2.45 (s, 2 H), 2.25 (br d, J=14 Hz, 2 H), 1.61 (m, 2H), 1.37 (m, 2 H), 1.27 (m, 2 H), 1.03 (m, 1 H), 0.87 (s, 9 H). ¹³C NMR(125 MHz, CDCl₃, ppm) δ 192.6, 161.1, 105.7, 81.4, 48.2, 47.0, 34.5,32.3, 27.5, 21.9.

Minor isomer: ¹H NMR (500 MHz, CDCl₃, ppm) δ 7.26 (d, J=6 Hz, 1 H), 5.34(d, J=6 Hz, 1 H), 2.66 (s, 2 H), 2.18 (br d, J=12 Hz, 2 H), 1.40 (m, 7H), 0.86 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃, ppm) δ 192.7, 161.7, 105.4,83.9, 47.4, 42.9, 34.9, 32.2, 27.5, 23.3.

6f (6-methoxy-1-oxaspiro[5,5]undec-2-en-4-one): Flash column on silicagel (20% and 40% ethylacetate/hexane) gave 6f, as a 1.5:1 mixture ofdiastereomers (80 mg combined, 81%), both colorless oils. FIGS. 22 and23 of U.S. Pat. No. 7,230,125 show the ¹H NMR spectrum and ¹³C NMRspectrum, respectively, of the major isomer of spiro-dihydropyrone 6f.FIGS. 24 and 25 of U.S. Pat. No. 7,230,125 show the ¹H NMR spectrum and¹³C NMR spectrum, respectively, of the minor isomer ofspiro-dihydropyrone 6f.

Major isomer: ¹H NMR (500 MHz, CDCl₃, ppm) δ 7.23 (d, J=6 Hz, 1 H), 5.35(d, J=6 Hz, 1 H), 3.40 (t, J=4 Hz, 1 H), 3.39 (s, 3 H), 2.92 (d, J=17Hz, 1 H), 2.49 (d, J=17 Hz, 1 H), 2.00 (m, 1 H), 1.82 (m, 1 H), 1.59 (m,4 H), 1.37 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃, ppm) δ 192.5, 160.8,105.6, 84.9, 80.2, 57.6, 40.4, 30.6, 25.7, 21.2, 21.0.

Minor isomer: ¹H NMR (500 MHz, CDCl₃, ppm) δ 7.29 (d, J=6 Hz, 1 H), 5.35(d, J=6 Hz, 1 H), 3.42 (s, 3 H), 3.28 (d, J=13.5 Hz, 3 H), 3.01 (dd,J=11, 4 Hz, 1 H), 2.37 (br d, J=14 Hz, 1 H), 2.17 (d, J=13.5 Hz, 1 H),1.98 (dq, J=13, 4 Hz, 1 H), 1.83 (m, 1 H), 1.72 (qd, J=11, 4 Hz, 1 H).1.47 (m, 2 H), 1.32 (m, 1 H), 1.16 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃,ppm) δ 192.7, 160.8, 105.5, 83.5, 82.5, 57.4, 43.3, 31.2, 24.6, 23.5,20.4.

6g (N-Benzyloxycarbonyl-8-aza-1-oxaspiro[5,5]undec-2-en-4-one): Flashcolumn on silica gel (70% ethylacetate/hexane) gave 124 mg (82%) of theproduct, 6g. FIGS. 26 and 27 of U.S. Pat. No. 7,230,125 show the ¹H NMRspectrum and ¹³C NMR spectrum, respectively, of spiro-dihydropyrone 6g.

¹H NMR (500 MHz, CDCl₃, ppm) δ 7.35 (m, 5 H), 7.26 (d, J=6 Hz, 1 H),5.42 (d, J=6 Hz, 1 H), 5.13 (s, 2 H), 3.97 (br, 2 H), 3.22 (br, 2 H),2.52 (s, 2 H), 2.09 (br d, J=8 Hz, 2 H), 1.57 (br, 2 H). ¹³C NMR (125MHz, CDCl₃, ppm) δ 191.1, 160.4, 155.1, 136.5, 128.4, 128.1, 127.9,106.3, 79.8, 67.2, 47.1, 39.3, 33.5.

6h (1-oxaspiro[5,5]deca-2-en-4-one): Flash column on silica gel (12%ethylacetate/hexane) gave 31 mg (41%) of the product, 6h, as a colorlessoil. FIGS. 28 and 29 of U.S. Pat. No. 7,230,125 show the ¹H NMR spectrumand ¹³C NMR spectrum, respectively, of spiro-dihydropyrone 6h.

¹H NMR (500 MHz, CDCl₃, ppm) δ 7.22 (d, J=6 Hz, 1 H), 5.39 (d, J=6 Hz, 1H), 2.62 (s, 2 H), 2.12 (m, 2 H), 1.83 (m, 2 H), 1.72 (m, 2 H), 1.62 (m,2 H). ¹³C NMR (125 MHz, CDCl₃, ppm) δ 192.7, 161.9, 106.2, 92.0, 45.9,37.4, 23.7.

6i 2,2-dimethyl-2,3-dihydro-pyran-4-one: Bulb to bulb distillation (60°C./8 mm Hg, ot) afforded 25 mg (40%) product 61 as colorless oil. FIGS.30 and 31 of U.S. Pat. No. 7,230,125 show the ¹H NMR spectrum and ¹³CNMR spectrum, respectively, of dihydropyrone 6i.

¹H NMR (500 MHz, CDCl₃, ppm) δ 7.22 (d, J=6 Hz, 1 H), 5.38 (d, J=6 Hz, 1H), 2.52 (s, 2 H), 1.44 (s, 6 H). ¹³C NMR (125 MHz, CDCl₃, ppm) δ 192.4,161.5, 105.3, 81.4, 48.0, 26.1.

6j 2-methoxy-2-methyl-2,3-dihydro-pyran-4-one: ¹H NMR (500 MHz, CDCl₃,ppm) δ 7.24 (d, J=6 Hz, 1 H), 5.38 (d, J=6 Hz, 1 H), 3.49 (d, J=10 Hz, 1H), 3.43 (s, 3 H), 3.42 (d, J=10 Hz, 1 H), 2.87 (d, J=16.5 Hz, 1 H),2.33 (d, J=16.5 Hz, 1 H), 1.39 (s, 3 H) ¹³C NMR (125 MHz, CDCl₃, ppm) δ192.0, 161.1, 105.6, 82.7, 76.9, 59.6, 43.2, 20.7. FIGS. 32 and 33 ofU.S. Pat. No. 7,230,125 show the ¹H NMR spectrum and ¹³C NMR spectrum,respectively, of dihydropyrone 6j.

6k (2-t-butyl-2,3-dihydro-pyran-4-one): Flash column on silica gel (15%ethylacetate/hexane) gave 60 mg (78%) of the product, 6k, a slightlyyellow oil. FIGS. 34 and 35 of U.S. Pat. No. 7,230,125 show the ¹H NMRspectrum and ¹³C NMR spectrum, respectively, of dihydropyrone 6k.

¹H NMR (500 MHz, CDCl₃, ppm) δ 7.41 (dd, J₁˜0 Hz, J₂=4 Hz, 1H), 5.40(dd, J₁=1 Hz, J₂=5 Hz, 1H), 4.03 (dd, J₁=3 Hz, J₂=15 Hz, 1H), 2.53 (dd,J₁=15 Hz, J₂=16 Hz, 1H), 2.39 (ddd, J₁=1 Hz, J₂=3 Hz, J₁=16 Hz, 1H),1.00 (s, 9H). ¹³C NMR (125 MHz, CDCl₃, ppm) δ 193.6, 163.8, 106.6, 86.9,37.2, 33.8, 25.4.

General Procedure for Enantioselective HDA Reactions Shown in Table 4

General: All liquid aldehydes were distilled prior to use. All solidaldehydes were recrystallized prior to use. PhCH₃ and CH₂Cl₂ weredistilled over CaH₂. Acetyl chloride was distilled fromN,N-dimethylaniline just prior to use. Melting points are uncorrectedand were measured on a Fisher-Johns melting point apparatus. ¹H and ¹³CNMR were recorded at 400 or 500 MHz and 100 or 125 MHz respectively on aBruker DRX-400 or 500 spectrometer. Proton chemical shifts wereinternally referenced to the residual proton resonance in CDCl₃ (δ7.26). Carbon chemical shifts were internally referenced to thedeuterated solvent signals in CDCl₃ (δ 77.00). Infrared spectra wereobtained on a Nicolet 20 SXB FT-IR spectrometer. Silica gel (60 Å,230-400 mesh) was obtained from Silicycle and used as received.

Procedure: To a solution of the aldehyde (1.0 mmol) and(4R,5R)-2,2-dimethyl-α,α,α′α′-tetra(naphtha-1-yl)-1,3-dioxolan-4,5-dimethanol(2) (Beck, A. K.; Bastani, B.; Plattner, D. A.; Petter, W.; Seebach, D.;Braunschweiger, H.; Gysi, P.; La Vecchia, L. Chimia, 1991, 45, 238) (0.1mmol) in PhCH₃ (0.5 mL) at −78° C. (dry-ice/acetone cooling bath) wasadded (E)-1-dimethylamino-3-tert-butyldimethylsiloxy-1,3-butadiene (1)(Kozmin, S. A.; Janey, J. M.; Rawal, V. H. J. Org. Chem. 1999, 64, 3039)(0.5 mmol) dropwise. The resulting reaction mixture was kept at theindicated temperature for the specified period of time (Table 4). Themixture was then recooled to −78° C. prior to dilution with CH₂Cl₂ (1.0mL). Freshly distilled acetyl chloride (1.0 mmol) was then added and thereaction mixture stirred at −78° C. for 15 min. The crude mixture wassubsequently transferred directly on top of a silica gel column andeluted with EtOAc/hexanes to afford the desired dihydropyran-4-one.

4a ((S)-2,3-Dihydro-2-phenyl-4H-pyran-4-one), (Bednarski, M.;Danishefsky, S. J. J. Am. Chem. Soc., 1986, 108, 7060; Corey, E. J.;Cywin, C. L.; Roper, T. D. Tetrahedron Lett., 1992, 33, 6907):

4a was isolated as a clear, colorless oil: >98% ee [Chiralcel OD-H,hexane:i-propanol=10:1, 0.9 mL/min, t_(R) (major) 12.9 min, t_(R)(minor) 15.0 min]; [α]_(D) ²⁴=+95.6° (c 0.35, CHCl₃); ¹H NMR (CDCl₃, 500MHz) δ 7.59 (1H, d, J=6.5 Hz), 7.43 (5H, m), 5.54 (1H, dd, J=6.5, 1.0Hz), 5.43 (1H, dd, J=14.0, 4.5 Hz), 2.92 (1H, dd, J=17.0, 14.0 Hz), 2.67(1H, ddd, J=17.0, 4.5, 1.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 192.2, 163.2,137.8, 128.9, 128.8, 126.1, 107.4, 81.1, 43.4; IR (film) ν 1676, 1595,1403, 1269, 1228 cm⁻¹. FIG. 36 of U.S. Pat. No. 7,230,125 shows an HPLCscan of a single enantiomer of 4a and FIG. 37 of U.S. Pat. No. 7,230,125shows an HPLC scan of racemic 4a.

4b (2,3-Dihydro-2-(4-Methoxyphenyl)-4H-pyran-4-one), (Wang, B.; Feng,X.; Huang, Y.; Liu, H.; Cui, X.; Jiang, Y. J. Org. Chem., 2002, 67,2175):

4b was isolated as a clear, colorless crystalline solid: 94% ee[Chiralcel OD-H, hexane:i-propanol=9:1, 0.5 mL/min, t_(R) (major) 28.5min, t_(R) (minor) 32.0 min]; [α]_(D) ²⁴=+148.2° (c 0.29, CHCl₃);m.p.=48-49° C. (CHCl₃); ¹H NMR (CDCl₃, 500 MHz) δ 7.45 (1H, d, J=6.0Hz), 7.32 (2H, d, J=8.5 Hz), 6.93 (2H, d, J=8.5 Hz), 5.50 (1H, dd,J=6.0, 1.0 Hz), 5.36 (1H, dd, J=14.5, 3.5 Hz), 3.18 (3H, s), 2.92 (1H,dd, J=17.0, 14.5 Hz), 2.61 (1H, ddd, J=17.0, 3.5, 1.0 Hz); ¹³C NMR(CDCl₃, 125 MHz) δ 192.35, 163.24, 159.97, 129.71, 127.67, 114.07,107.13, 80.79, 55.24, 43.05; IR (KBr) ν 3067, 2965, 2935, 2906, 2875,2837, 1661, 1592, 1517, 1453, 1411, 1284, 1259, 1229, 1210, 1172, 1111,1031, 991, 944, 931, 869, 819, 791 cm⁻¹. FIG. 38 of U.S. Pat. No.7,230,125 shows an HPLC scan of a single enantiomer of 4b and FIG. 39 ofU.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4b.

4c (2-(3-Bromophenyl)-2,3-dihydro-4H-pyran-4-one), (Long, J.; Hu, J.;Shen, X.; Ji, B.; Ding, K. J. Am. Chem. Soc., 2002, 124; Aikawa, K.;Irie, R.; Katsuki, T. Tetrahedron, 2001, 57, 845):

N.B.:(4S,5S)-2,2-Dimethyl-α,α,α′α′-tetra(naphtha-1-yl)-1,3-dioxolan-4,5-dimethanol(ent-2) was used as the catalyst. 4c was isolated as a pale yellow oil:97% ee [Chiralcel OD-H, hexane:i-propanol=19:1, 1.0 mL/min, t_(R)(minor)=9.3 min, t_(R) (major)=12.0 min]; [α]_(D) ²⁵=−73.9° (c 1.06,CHCl₃); ¹H NMR (CDCl₃, 500 MHz) δ 7.58 (1H, m), 7.52 (1H, dt, J=7, 2Hz), 7.48 (1H, d, J=7 Hz), 7.28 (2H, m), 5.54 (1H, dd, J=6, 1 Hz), 5.40(1H, dd, J=15, 4 Hz), 2.86 (1H, dd, J=16, 14 Hz), 2.67 (1H, ddd, J=16,4, 1 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 191.4, 162.8, 140.1, 132.0, 130.4,129.2, 124.5, 122.9, 107.6, 80.1, 43.3; IR (film) ν 1683, 1593, 1402,1270, 1226, 1038 cm⁻¹. FIG. 40 of U.S. Pat. No. 7,230,125 shows an HPLCscan of a single enantiomer of 4c and FIG. 41 of U.S. Pat. No. 7,230,125shows an HPLC scan of racemic 4c.

4d (2,3-Dihydro-2-(4-trifluoromethylphenyl)-4H-pyran-4-one), (Kezuka,S.; Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T. Bull. Chem. Soc. Jpn.,2001, 74, 1333):

4d was isolated as a clear, colorless crystalline solid: 95% ee[Chiralcel OD-H, hexane:i-propanol=10:1, 0.9 mL/min, t_(R) (major) 12.2min, t_(R) (minor) 16.1 min]; [α]_(D) ²³=+77.2° (c 0.31, CHCl₃);m.p.=44-45° C. (CHCl₃); ¹H NMR (CDCl₃, 500 MHz) δ 7.68 (2H, d, J=8.0Hz), 7.53 (2H, d, J=8.0 Hz), 7.49 (1H, d, J=6.0 Hz), 5.55 (1H, dd,J=6.0, 1.0 Hz), 5.49 (1H, dd, J=14.5, 3.5 Hz), 2.85 (1H, dd, J=17.0,14.5 Hz), 2.69 (1H, ddd, J=17.0, 3.5, 1.0 Hz); ¹³C NMR (CDCl₃, 125 MHz)δ 191.27, 162.81, 141.78, 130.98 (q, J=32.6 Hz), 126.23, 125.84 (q,J=3.8 Hz), 124.87, 107.65, 80.16, 43.37; IR (KBr) ν 3070, 3059, 2953,2870, 1675, 1597, 1584, 1410, 1326, 1275, 1232, 1212, 1167, 1125, 1068,1041, 1019, 940, 841 cm⁻¹. FIG. 42 of U.S. Pat. No. 7,230,125 shows anHPLC scan of a single enantiomer of 4d and FIG. 43 of U.S. Pat. No.7,230,125 shows an HPLC scan of racemic 4d.

4e (2,3-Dihydro-2-(1-naphthyl)-4H-pyran-4-one), (Long, J.; Hu, J.; Shen,X.; Ji, B.; Ding, K. J. Am. Chem. Soc., 2002, 124; Aikawa, K.; Irie, R.;Katsuki, T. Tetrahedron, 2001, 57, 845):

4e was isolated as a pale, yellow oil: 99% ee [Chiralcel OD-H,hexane:i-propanol=20:1, 1.4 mL/min, t_(R) (major) 30.2 min, t_(R)(minor) 37.3 min]; [α]_(D) ²³=−104.1° (c 0.30, CHCl₃); ¹H NMR (CDCl₃,500 MHz) δ 7.98 (1H, d, J=8.0 Hz), 7.95-7.87 (2H, m), 7.66 (1H, d, J=6.5Hz), 7.60-7.50 (4H, m), 6.18 (1H, dd, J=14.0, 3.5 Hz), 5.62 (1H, dd,J=6.0, 1.0 Hz), 3.08 (1H, dd, J=17.0, 14.0 Hz), 2.87 (1H, ddd, J=17.0,3.5, 1.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 192.33, 163.37, 133.76, 133.20,129.98, 129.50, 129.08, 126.73, 126.00, 125.25, 123.84, 122.54, 107.49,78.39, 42.68; IR (film) ν 3053, 2967, 2921, 1669, 1590, 1513, 1403,1339, 1270, 1223, 1183, 1037, 983, 932, 863, 800, 776 cm⁻¹. FIG. 44 ofU.S. Pat. No. 7,230,125 shows an HPLC scan of a single enantiomer of 4eand FIG. 45 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4e.

4f (2,3-Dihydro-2-(2-naphthyl)-4H-pyran-4-one), (Hanamoto, T.; Furuno,H.; Sugimoto, Y.; Inanaga, J. Synlett, 1997, 79):

4f was isolated as a pale yellow, crystalline solid: 94% ee [ChiralcelOD-H, hexane:i-propanol=9:1, 1.0 mL/min, t_(R) (major) 24.2 min, t_(R)(minor) 39.6 min]; [α]_(D) ²⁵=+110.4° (c 0.13, CHCl₃); mp=115-117° C.(EtOAc/hexanes); ¹H NMR (CDCl₃, 400 MHz) δ 7.92-7.83 (4H, m), 7.56-7.46(4H, m), 5.60-5.54 (2H, m), 2.99 (1H, dd, J=17.0, 14.5 Hz), 2.74 (1H,ddd, J=8.5, 3.5, 1.0 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ 192.11, 163.25,135.19, 133.39, 133.09, 128.85, 128.18, 127.83, 126.72, 126.68, 125.46,123.57, 107.46, 81.20, 43.41; IR (KBr) ν 3054, 2917, 1661, 1592, 1403,1268, 1222, 1041, 991, 927, 900, 864, 825, 749 cm⁻¹. FIG. 46 of U.S.Pat. No. 7,230,125 shows an HPLC scan of a single enantiomer of 4f andFIG. 47 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4f.

4g (S)-2,3-Dihydro-2-(2-furyl)-4H-pyran-4-one (Wang, B.; Feng, X.;Huang, Y.; Liu, H.; Cui, X.; Jiang, Y. J. Org. Chem., 2002, 67, 2175;Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K. J. Am. Chem. Soc., 2002,124, 10; Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem.,1998, 63, 403):

4g was isolated as a pale yellow, crystalline solid: 92% ee [ChiralcelOD-H, hexane:i-propanol=9:1, 0.5 mL/min, t_(R) (minor) 22.7 min, t_(R)(major) 24.2 min]; [α]_(D) ²⁵=+342.1° (c 0.10, CHCl₃); m.p.=67-69° C.(EtOAc/hexanes); ¹H NMR (CDCl₃, 500 MHz) δ 7.48 (1H, dd, J=2.0, 1.0 Hz),7.38 (1H, d, J=6.0 Hz), 6.46 (1H, d, J=4.0 Hz), 6.41 (1H, dd, J=3.0,2.0), 5.51 (1H, dd, J=6.0, 1.0 Hz), 5.48 (1H, dd, J=13.5, 4.0 Hz), 3.10(1H, dd, J=17.0, 13.5 Hz), 2.74 (1H, ddd, J=17.0, 4.0, 1.0 Hz); ¹³C NMR(CDCl₃, 125 MHz) δ 191.3, 162.4, 150.0, 143.6, 110.6, 109.7, 107.4,73.5, 39.5; IR (KBr) ν 1677, 1596, 1403, 1272, 1209 cm⁻¹. FIG. 48 ofU.S. Pat. No. 7,230,125 shows an HPLC scan of a single enantiomer of 4gand FIG. 49 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4g.

4h ((S)-2-Cyclohexyl-2,3-Dihydro-4H-pyran-4-one), (Corey, E. J.; Cywin,C. L.; Roper, T. D. Tetrahedron Lett., 1992, 33, 6907; Aikawa, K.; Irie,R.; Katsuki, T. Tetrahedron, 2001, 57, 845):

4h was isolated as a clear, pale yellow oil: 87% ee [Chiralcel OD-H,hexane:i-propanol=10:1, 0.2 mL/min, t_(R) (major) 31.1 min, t_(R)(minor) 33.5 min]; [α]_(D) ²⁵=+157.2° (c 0.41, CHCl₃); ¹H NMR (CDCl₃,500 MHz) δ 7.36 (1H, d, J=6.0 Hz), 5.38 (1H, dd, J=6.0, 1.0 Hz), 4.16(1H, ddd, J=14.5, 5.5, 3.0 Hz), 2.54 (1H, dd, J=16.5, 14.5 Hz), 2.38(1H, ddd, J=16.5, 3.0, 1.0 Hz), 1.91-1.84 (1H, m), 1.83-1.75 (2H, m),1.74-1.62 (3H, m), 1.31-1.00 (5H, m); ¹³C NMR (CDCl₃, 125 MHz) δ 193.30,163.59, 106.79, 83.55, 41.34, 39.07, 28.11, 27.99, 26.19, 25.83, 25.76;IR (film) ν 3050, 2928, 2854, 1681, 1596, 1450, 1407, 1278, 1215, 1189,1038, 993, 910, 793 cm⁻¹. FIG. 50 of U.S. Pat. No. 7,230,125 shows anHPLC scan of a single enantiomer of 4h and FIG. 51 of U.S. Pat. No.7,230,125 shows an HPLC scan of racemic 4h.

4i ((S)-2,3-Dihydro-2-n-propyl-4H-pyran-4-one), (Corey, E. J.; Cywin, C.L.; Roper, T. D. Tetrahedron Lett., 1992, 33, 6907):

4i was isolated as a clear, pale yellow oil: 83% ee [Chiralcel OD-H,hexane:i-propanol=99:1, 1.0 mL/min, t_(R) (major) 23.5 min, t_(R)(minor) 26.5 min]; [α]_(D) ²⁵=+159.7° (c 0.74, CHCl₃); ¹H NMR (CDCl₃,500 MHz) δ 7.32 (1H, d, J=6.0 Hz), 5.36 (1H, dd, J=6.0, 1.0 Hz), 4.37(1H, m), 2.47 (1H, dd, J=16.0 Hz, 12.5 Hz), 2.38 (1H, ddd, J=16.5, 4.0,1.0 Hz), 1.77 (1H, m), 1.61 (1H, m), 1.44 (2H, m), 0.93 (3H, t, J=7.5Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 192.8, 163.3, 106.9, 79.3, 41.8, 36.4,18.0, 13.7; IR (film) ν 1682, 1596, 1406, 1274, 1218, 1037 cm⁻¹. FIG. 52of U.S. Pat. No. 7,230,125 shows an HPLC scan of a single enantiomer of4i and FIG. 53 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic4i.

4j ((R)-2,3-Dihydro-2-[(E)-styryl]-4H-pyran-4-one), (Wang, B.; Feng, X.;Huang, Y.; Liu, H.; Cui, X.; Jiang, Y. J. Org. Chem., 2002, 67, 2175;Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K. J. Am. Chem. Soc., 2002,124, 10; Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem.,1998, 63, 403):

N.B.:(4S,5S)-2,2-Dimethyl-α,α,α′α′-tetra(naphtha-1-yl)-1,3-dioxolan-4,5-dimethanol(ent-2) was used as the catalyst. 4j was isolated as a clear, paleyellow oil: 95% ee [Chiralcel OD-H, hexane:i-propanol=4:1, 1.0 mL/min,t_(R) (minor) 12.8 min, t_(R) (major) 24.5 min]; [α]_(D) ²⁵=−187.0° (c0.58, CHCl₃); ¹H NMR (CDCl₃, 500 MHz) δ 7.41 (3H, m), 7.35 (2H, t, J=8.0Hz), 7.30 (1H, m), 6.72 (1H, d, J=16.0 Hz), 6.29 (1H, dd, J=16.0, 6.0Hz), 5.47 (1H, d, J=6.0 Hz), 5.08 (1H, m), 2.74 (1H, dd, J=17.0, 13.0Hz), 2.63 (1H, dd, J=17.0, 4.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 191.9,162.9, 135.6, 133.8, 128.7, 128.5, 126.8, 125.0, 107.3, 79.7, 42.0; IR(film) ν 1675, 1593, 1405, 1268, 1217, 1038 cm⁻¹. FIG. 54 of U.S. Pat.No. 7,230,125 shows an HPLC scan of a single enantiomer of 4j and FIG.55 of U.S. Pat. No. 7,230,125 shows an HPLC scan of racemic 4j.

General Procedure for TADDOL Catalyzed Diels-Alder Reactions Shown inTable 5

To a solution of the acrolein (0.5 mmol) and the TADDOL (0.1 mmol) inPhCH₃ (0.75 mL) at −80° C. was added(E)-1-dimethylamino-3-tert-butyldimethylsiloxy-1,3-butadiene (1.0 mmol)dropwise. The resulting reaction mixture was stirred for 48 h at −80° C.Lithium aluminum hydride (1.0 M in Et₂O, 2.0 mL, 2.0 mmol) was thenadded at −80° C. The reaction mixture was stirred for 1 h at −80° C. andanother 2 h at rt. The excess LiAlH₄ was carefully quenched with H₂O(0.5 mL) with frequent cooling of the mixture. The mixture was thendiluted with Et₂O (20 mL). The solids were filtered off and washed withEt₂O (3×5 mL). The combined organic filtrates were concentrated in vacuoto afford a clear, colorless oil. This was taken up in acetonitrile (3.0mL) and cooled in an ice-bath. HF (5% in CH₃CN, 0.75 mL) was then addedand the mixture stirred for 1 h at 0° C. The solvent was then removed invacuo and the residue chromatographed on silica gel to afford 503.

The enantiomeric excess was determined by Mosher ester analysis viaintegration of the aliphatic CH ₂O protons.

To a solution of the acrolein (0.5 mmol) and the TADDOL (0.1 mmol) inPhCH₃ (0.75 mL) at −80° C. was added(E)-1-dimethylamino-3-tert-butyldimethylsiloxy-1,3-butadiene (1.0 mmol)dropwise. The resulting reaction mixture was stirred for 48 h at −80° C.HF (5% in CH₃CN, 0.75 mL) was then added and the mixture stirred for 1 hat −80° C. and another 1 h at rt. The solvent was then removed in vacuoand the residue chromatographed on silica gel to afford 504.

General Procedure for TADDOL Catalyzed Diels-Alder Reactions Shown inTable 6

To a solution of the acrolein (1.0 mmol) and the TADDOL (0.1 mmol) inPhCH₃ (0.75 mL) at −80° C. was added (E)-1-diethylamino-1,3-butadiene(0.5 mmol) dropwise. The resulting reaction mixture was stirred for 78 hat −80° C. Lithium aluminum hydride (1.0 M in Et₂O, 2.0 mL, 2.0 mmol)was then added at −80° C. The reaction mixture was stirred for 1 h at−80° C. and another 2 h at rt. The excess LiAlH₄ was carefully quenchedwith H₂O (0.5 mL) with frequent cooling of the mixture. The mixture wasthen diluted with Et₂O (20 mL). The solids were filtered off and washedwith Et₂O (3×5 mL). The combined organic filtrates were concentrated invacuo to afford a clear, colorless oil. This was taken up inacetonitrile (3.0 mL) and cooled in an ice-bath. HF (5% in CH₃CN, 0.75mL) was then added and the mixture stirred for 1 h at 0° C. The solventwas then removed in vacuo and the residue chromatographed on silica gelto afford 507.

The enantiomeric excess was determined by Mosher ester analysis viaintegration of the aliphatic CH ₂O protons.

General Procedure for the Addition of Alkynes to Aldehydes as Shown inTable 7

To a solution of the TADDOL (0.1 mmol) in THF (3 mL) was addeddiethylzinc (1.0 M in THF, 2.0 mL, 2.0 mmol). After the mixture wasstirred for 1 h at rt, phenylacetylene (1.5 mmol) was added and thestirring continued for an additional 1 h. Benzaldehyde (1.0 mmol) wasthen added, and the reaction mixture was stirred for 18 h at rt. Thereaction was then quenched with 1 N HCl and extracted with CH₂Cl₂. Theorganic layer was washed with brine, dried (MgSO₄), and concentrated invacuo. Chromatography on silica gel then afforded the desired product.

The enantiomeric excess was determined by HPLC on a Chiralcel OD-Hcolumn.

The foregoing detailed description and accompanying drawings have beenprovided by way of explanation and illustration, and are not intended tolimit the scope of the appended claims. Many variations in the presentlypreferred embodiments illustrated herein will be obvious to one ofordinary skill in the art, and remain within the scope of the appendedclaims and their equivalents.

The invention claimed is:
 1. A method comprising combining ahetero-olefin, a metal-free chiral hydrogen-bond donor, and a reactantselected from the group consisting of a diene, an alkyne and anucleophile with a solvent to form a solution for a time sufficient toallow an enantioselective reaction; wherein said reaction is selectedfrom the group consisting of Diels-Alder reaction, dipolarcycloadditions, carbene addition, cyclopropanation, aziridination,nucleophilic substitution, nucleophilic addition to carbonyls,nucleophilic addition to alpha, beta-unsaturated carbonyls, nucleophilicaddition to imines, cyanohydrin formation, cyanoamine formation, andreductions; wherein said hetero-olefin has a functionality selected fromthe group consisting of an imine and a thioketone; and wherein saidsolution does not comprise a transition metal.
 2. The method of claim 1,wherein said solution does not comprise a Lewis acid.
 3. The method ofclaim 1, wherein said reaction is a Diels-Alder type reaction.
 4. Themethod of claim 1, wherein said reaction is a reduction.
 5. The methodof claim 1, wherein said reaction is a nucleophilic substitution.
 6. Themethod of claim 1, wherein said enantioselective synthesis results in anenantiomeric excess of at least 60%.
 7. The method of claim 1, whereinsaid enantioselective synthesis results in an enantiomeric excess of atleast 70%.
 8. The method of claim 1, wherein said enantioselectivesynthesis results in an enantiomeric excess of at least 80%.
 9. Themethod of claim 1, wherein said enantioselective synthesis results in anenantiomeric excess of at least 90%.
 10. The method of claim 1, whereinsaid enantioselective synthesis results in an enantiomeric excess of atleast 95%.
 11. The method of claim 1, wherein said chiral hydrogen-bonddonor has a stereogenic center and a hydrogen-heteroatom bond.
 12. Themethod of claim 11, wherein said hydrogen-heteroatom bond is betweenhydrogen and oxygen or between hydrogen and nitrogen.
 13. The method ofclaim 1, wherein said chiral hydrogen-bond donor has a stereogeniccenter and is selected from the group consisting of alcohols, phenols,carboxylic acid, carboxylic ester, amides, amines, amino acids, andpeptides.
 14. The method of claim 1, wherein said chiral hydrogen-bonddonor is a chiral alcohol.
 15. The method of claim 14 wherein saidchiral alcohol is a diol.
 16. The method of claim 14 wherein said chiralalcohol is a 1,4-diol.
 17. The method of claim 14 wherein said chiralalcohol is a tartaric acid ester.
 18. A method comprising combining ahetero-olefin, and a metal-free chiral hydrogen-bond donor, and a dienewith a solvent to form a solution for a time sufficient to allow anenantioselective reaction; wherein said reaction is selected from thegroup consisting of Diels-Alder reaction, dipolar cycloadditions,carbene addition, cyclopropanation, aziridination, nucleophilicsubstitution, nucleophilic addition to carbonyls, nucleophilic additionto alpha, beta-unsaturated carbonyls, nucleophilic addition to imines,cyanohydrin formation, cyanoamine formation, and reductions; and whereinsaid hetero-olefin has a functionality selected from the groupconsisting of an imine and a thioketone.
 19. The method of claim 18,wherein said diene has a heteroatom.
 20. The method of claim 18, whereinsaid diene has the structure C═C(R³)−C═C—Z, wherein R³ and Z haveheteroatoms.
 21. The method of claim 18 wherein said diene is a1,3-butadiene, wherein said 1,3 butadiene is substituted with anelectron donating group at a 3 position and an electron donating groupat a 1 position.
 22. The method of claim 21 wherein said electrondonating group at the 3 position has a protected alcohol.
 23. The methodof claim 21 wherein said electron donating group at the 1 position has asubstituted nitrogen.